1 Resistant Hypertension Resistant Hypertension Resistant Hypertension Resistant Hypertension Christopher Valentine, MD Program Director, Nephrology Fellowship Program Department of Internal Medicine Department of Internal Medicine Division of Nephrology The Ohio State University Wexner Medical Center Disclosures Disclosures • Drs. Valentine and Mazzaferri are site- PI’ f S li it HTN 3 d PI’s for Symplicity HTN-3 and Symplicity HTN-4 trials at the The Ohio State University’s Wexner Medical Center • Identified slides from Dr. Mazzaferri’s talk adapted from Symplicity HTN slide deck (permission from Medtronic, Inc.)
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Christopher Valentine, MDProgram Director, Nephrology Fellowship Program
Department of Internal MedicineDepartment of Internal MedicineDivision of Nephrology
The Ohio State University Wexner Medical Center
DisclosuresDisclosures
• Drs. Valentine and Mazzaferri are site-PI’ f S li it HTN 3 dPI’s for Symplicity HTN-3 and Symplicity HTN-4 trials at the The Ohio State University’s Wexner Medical Center
• Identified slides from Dr. Mazzaferri’s talk adapted from Symplicity HTN slide deck (permission from Medtronic, Inc.)
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ObjectivesObjectives• Define Resistant Hypertension• Review JNC 8 thresholds for treatment• Discuss lifestyle modification• Review common secondary causes of
hypertension• Discuss pharmacotherapy of resistant
hypertension• Introduction to Catheter based renal• Introduction to Catheter based renal
denervation– Evidence, trial, data– Late Breaking news on Renal Denervation
• BP above goal in spite of concurrent use of 3 g pantihypertensive agents of different classes.
• One should be a diuretic.
• All should be at optimal doses.
• Includes patients who are controlled on 4 or more meds.
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Uncontrolled HTNUncontrolled HTN
• Less specific term than RH• Less specific term than RH
• Also includes those who are not compliant or who are on an inadequate regimen
JNC 8JNC 8
• Recommendation 1
• In the general population aged ≥60 years, initiate pharmacologic treatment to lower blood pressure (BP) at systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg and treatblood pressure (DBP) ≥90 mm Hg and treat to a goal SBP <150 mm Hg and goal DBP <90 mm Hg. (Strong Recommendation –Grade A)
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JNC 8JNC 8
• Recommendation 2
• In the general population <60 years, initiate pharmacologic treatment to lower BP at DBP ≥90 mm Hg and treat to a goal DBP <90 mm Hg. (For ages 30-59 years, Strong Recommendation – Grade A; For ages 18-; g29 years, Expert Opinion – Grade E)
JNC 8JNC 8• Recommendation 3
I th l l ti <60 i iti t• In the general population <60 years, initiate pharmacologic treatment to lower BP at SBP ≥140 mm Hg and treat to a goal SBP <140 mm Hg. (Expert Opinion – Grade E)
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JNC 8JNC 8
• Recommendation 4
I th l ti d ≥18 ith• In the population aged ≥18 years with chronic kidney disease (CKD), initiate pharmacologic treatment to lower BP at SBP ≥140 mm Hg or DBP ≥90 mm Hg and treat to goal SBP <140 mm Hg and goal DBP <90 mm Hg. (Expert Opinion –Grade E)
Prevalence of RHPrevalence of RH• Truly not known
• ALLHAT was ethnically diverse and included 33,000 people
– 27% required 3 or more meds
– 49% controlled on 1 or 2 meds– 49% controlled on 1 or 2 meds
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SBP vs DBPSBP vs DBP• SBP is harder to control, and this gets
worse with age.
• Framingham:
– 90% achieved DBP goal of < 90mmHg
– 49% achieved SBP <140mmHg
– Strongest predictor of lack of BP control was age
– LVH and obesity also associated with poor control
Patient Characteristics Associated With RH
Patient Characteristics Associated With RH
• Older age • Obesity• High baseline BP
• Excessive dietary Na intake
• CKD – Cr > 1.5
Obesity
• DM
• LVH
• Black race
• Female sex(Strongest predictor in ALLHAT)
Female sex
• Residence in Southeast US
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AdherenceAdherence
• 40% of patients with a new Dx of HTN will stop their medications within a year
• At 5-10 yr follow up, less than 40% take their prescribed meds
LifestyleLifestyle• Healthy diet, weight control, and exercise
should be emphasized.
• Typical American sodium intake is much higher than 2 g a day
• Cessation of heavy ETOH intake reduced 24h SBP by 7 mmHg and DBP by 7mmHG, and reduced prevalence of HTN from 42% to 12%.
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Treatment: LifestyleTreatment: Lifestyle• 10 kg wt loss associated with 6/4.6 mmHg
decrease in BP
• Salt restriction can reduce BP by 5-10/2-6 mmHg
• Limit ETOH to 1-2 drinks/day
• DASH diet led to improvement in BP by 11/5.5 mmHg.
– High fiber low fat diet. Rich in fruits, vegetables, low fat dairy products.
Medications That May Elevate Blood PressureMedications That May
• Adverse effect of other meds?Adverse effect of other meds?
• If none of above are true, look for secondary causes.
24 hr ambulatory BP monitoring
24 hr ambulatory BP monitoring
• Mean ambulatory daytime BP >135/85 is y yconsidered elevated.
• If white coat effect is confirmed, treatment should be adjusted based on out-of-office BPBP.
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Secondary Causes of RHSecondary Causes of RH• 12.7% of patients over age 50 referred to a
HTN clinic had a secondary cause.
• Common
– Renal artery stenosis
– Primary Aldosteronismy
– Chronic kidney disease
– Obstructive sleep apnea
Renal Artery StenosisRenal Artery Stenosis
• CORAL Study NEJM Nov 18, 2013.
• 947 patients
• Medical therapy plus renal artery stenting vs. medical therapy
• 43 month follow up
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RAS - CORAL STUDYRAS - CORAL STUDY
• Medical Therapy:
– ARB– ARB
– With or without thiazide type diuretic
– Add amlodipine if needed
– Antiplatelet therapy
Statin– Statin
RAS - CORAL StudyRAS - CORAL Study• Rate of primary composite endpoint did
not differ (35.1% in stent group vs 35.8%).
• No significant difference in individual components of the endpoint – e.g. death from CV or renal cause, stroke, MI, CHF,
i l i ffi i ESRDprogressive renal insufficiency, ESRD.
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RAS – CORAL StudyRAS – CORAL Study
I th l ti RAS ith HTN CKD• In atherosclerotic RAS with HTN or CKD, renal artery stenting did not confer significant benefit when added to comprehensive medical therapy.
Obstructive Sleep ApneaObstructive Sleep Apnea
• In studies of RH, 80 - 90 % have obstructive sleep apnea.p p
• More common and severe in men.
• Intermittent hypoxemia and/or increasedIntermittent hypoxemia and/or increased upper airway resistance cause increased sympathetic nervous system activity.
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Treatment: CPAP for obstructive sleep apnea
Treatment: CPAP for obstructive sleep apnea• Mixed results, but some studies show
9-14 mmHg decrease in SBP and 7-9 mmHg decrease in DBP.
Ernest Mazzaferri Jr., MDMedical Director, Richard M. Ross Heart Hospital
Associate Professor - ClinicalAssociate Professor - ClinicalDepartment of Cardiovascular Medicine
The Ohio State University Wexner Medical Center
Introduction to Catheter based renal
denervation
Introduction to Catheter based renal
denervationdenervationdenervation
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Resistant Hypertension Resistant Hypertension
Causes of PseudoresistantHypertension1,2
However, a majority of
patients with resistant
hypertension
Secondary Causes of Hypertension1,2
Suboptimal dosing of antihypertensive agents
White coat effect
Suboptimal BP measurement technique
Physician inertia
Lifestyle factors
hypertension and
no identifiable secondary
causes have an activated
sympathetic nervous system
d i d
Obstructive sleep apnea
Primary aldosteronism
Renal artery stenosis
1. Calhoun DA, et al. Circulation. 2008;117;e510-e526.2. Makris A, et al. Int J Hypertens. 2011;doi: 10.4061/2011/598694.3. Papademetriou V, et al. Int J Hypertens. 2011;doi:10.4061/2011/196518.
Lifestyle factors
Medications that interfere with BP control
Pseudoresistance caused by poor adherence to prescribed medication
and increased sympathetic
outflow3
The Sympathetic Nervous SystemThe Sympathetic Nervous System
• The SNS supplies catabolic signals to the body, acting whenever rapid response to the environment is needed
Dil t il• Functions include:– Accelerating the
heart– Dilating coronary
vessels– Increasing arterial BP
Emptying blood
Dilates pupils
Inhibits salivation
Relaxes bronchi
Accelerates heart
Inhibits digestive activity
S i l l
Cer
vic
alT
ho
raci
c
– Emptying blood reservoirs
– Dilating bronchi– Releasing glucose– Inhibiting GI activity
Adapted from Campbell WW. DeJong’s The Neurologic Examination: Incorporating the Fundamentals of Neuroanatomy and Neurophysiology. 6th ed. 2005.
Epinephrine—adrenal glandsNorepinephrine—kidney
Stimulates glucose release by liver
Relaxes bladder
Contracts rectum
Lu
mb
ar
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Blood Pressure Neurohormones
Chronic Effect of IncreasedSympathetic Nerve ActivityChronic Effect of IncreasedSympathetic Nerve Activity
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
Blood Pressure Neurohormones
Chronic Effect of IncreasedSympathetic Nerve ActivityChronic Effect of IncreasedSympathetic Nerve Activity
Wall Thickness Compliance
Atherosclerosis
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
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Blood Pressure Neurohormones
Chronic Effect of IncreasedSympathetic Nerve ActivityChronic Effect of IncreasedSympathetic Nerve Activity
HypertrophyIschemia
ArrhythmiaHeart Failure
Worsening HF
Wall Thickness Compliance
Atherosclerosis
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
Blood Pressure Neurohormones
Chronic Effect of IncreasedSympathetic Nerve ActivityChronic Effect of IncreasedSympathetic Nerve Activity
HypertrophyIschemia
ArrhythmiaHeart Failure
Worsening HF
Wall Thickness Compliance
Atherosclerosis
GFRIschemia
Kidney FailureWorsening Kidney Failure
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
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Renal DenervationRenal Denervation
Blood Pressure Neurohormones
Disrupt the renal nerves,break the cycle
Simultaneously reduce both efferent & afferent
effects
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
Renal DenervationRenal Denervation
Blood Pressure Neurohormones
Disrupt the renal nerves,break the cycle
Simultaneously reduce both efferent & afferent
effects
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
Mortality improvedRISKS: Operative morbidity and mortality
(abandoned in 1970’s)(abandoned in 1970 s)
1. Grimson KS. Total thoracic and partial to total lumbar sympathectomy and celiac ganglionectomy in the treatment of hypertension. Ann Surg 1941;114:753–75.2. Peet M, Woods W, Braden S. The surgical treatment of hypertension: results in 350 consecutive cases treated by bilateral supradiaphragmatic splanchnicectomy and lower dorsal sympathetic gangliectomy. Clinical lecture at New York session. JAMA 1940;115:1875– 85.3. Smithwick RH. Surgery in hypertension. Lancet 1948;2:65.4. Grimson KS, Orgain ES, Anderson B, Broome RA, Longino FH. Results of treatment of patients with hypertension by total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiacganglionectomy. Ann Surg 1949;129:850 –71.5. Evelyn KA, Alexander F, Cooper SR. Effect of sympathectomy on blood pressure in hypertension: a review of 13 years’ experience of the Massachusetts General Hospital. JAMA 1949;140:592– 602.6. Hinton JW. End results of thoracolumbar sympathectomy for advanced essential hypertension. Bull N Y Acad Med 1948;24:239 –52.7. Hammarstrom S, Bechgaard P. Prognosis in arterial hypertension: comparison between 251 patients after sympathectomy and selected series of 435 non-operated patients. Am J Med 1950;8:53– 6.
Targeting Renal NervesTargeting Renal Nerves•Nerves arise from T10‐L2•The nerves arborize around the artery and primarily lie
Vessel Lumen
Media
within the adventitia
Adventitia
Renal Nerves
Slide courtesy of. Medtronic, Inc.,
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Renal Nerve Anatomy Allows a Catheter-Based Approach
Renal Nerve Anatomy Allows a Catheter-Based Approach
Standard interventional technique• Standard interventional technique• 4-6 120-second treatments per artery• RFA: heat generated from high
frequency alternating current Data on file. Medtronic, Inc.
Catheter Based Renal Denervation
Catheter Based Renal Denervation
Catheter-based renal denervation for reduction of blood pressure in patients with treatment-resistant hypertension has seized the first place on a “Top 10 Medical Innovations List”.
Cl l d Cli i M di l I i S i 2012~Cleveland Clinic Medical Innovations Summit 2012
Data on file. Medtronic, Inc.
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Radio Frequency-Based Renal Denervation Systems
Radio Frequency-Based Renal Denervation Systems
A S li it ™
• Standard interventional technique• Tissue Temp > 50° C, irreversible damage to adjacent nerve fibers• RF Energy: heat generated from high frequency alternating current
A. Symplicity™– Medtronic,
Santa Rosa CAB. EnligHTN
– St. Jude Medical, St Paul, MN
C. V2 (Vessix)B t S i tifi C– Boston Scientific Co, Natick, MA
D. OneShot– Maya Medical,
Campbell, CACardiovascular Revascularization Medicine 14 (2013) 229–235
Ultrasound Energy-Based Renal Denervation
Ultrasound Energy-Based Renal Denervation
A PARADISE™ (P t R l
• Standard catheter based interventional technique• High-frequency sound waves cause frictional heating in tissue • Temperature ↑sufficient to cause injury to the renal nerves
A. PARADISE™ (Percutaneous Renal Denervation System)
– ReCor Medical, Ronkonkoma NY
B. TIVUS system
– Cardiosonic, Tel Aviv, Israel
In development:
Cardiovascular Revascularization Medicine 14 (2013) 229–235
In development:
Beta radiation/Beta-Cath
Drug-based Renal Denervation Local delivery
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First to Trial: Symplicity Investigational Catheter Device
First to Trial: Symplicity Investigational Catheter Device
• Generator will automatically control RF energy delivery:
– Power automatically ramped and maintained (5-8W)
– Continuously monitors temperature and impedanceContinuously monitors temperature and impedance
– Automatically shuts off after 120 seconds or when either impedance or temperature exceed program limits
– Multicenter - randomized, controlled study (no sham procedure)
– 106 patients with treatment-resistant hypertensionp yp– Intervention group (endovascular catheter-based RDN
with the Symplicity® Renal Denervation System™ plus baseline antihypertensive medications)
– Control group (baseline antihypertensive medications alone)
– 6 months (for the primary endpoint) with follow-up to 3 yearsP i d i t b t h i– Primary endpoint: between-group changes in average office SBP from baseline to 6 months
• Study ObjectiveT d t t th t th t b d l d ti i– To demonstrate that catheter-based renal denervation is a safe and effective treatment for uncontrolled hypertension
• Study Population– Uncontrolled hypertension population
• Study Objective– To demonstrate that catheter-based renal denervation is a
safe and effective treatment for uncontrolled hypertension
• Study Population– Uncontrolled hypertension population
• Office BP 140 ≤ SBP < 160 mmHg despite maximally tolerated doses of at least 3 antihypertensive medication classes
• Without significant renal impairment (eGFR ≥• Without significant renal impairment (eGFR ≥ 30mL/min)
• 24 ABPM average SBP ≥ 135 mmHg– 580 randomized subjects at up to 100 sites
• Randomization (2:1)• All patients maintained on baseline meds for 6 months
• Enrollment closed January 9, 2014
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Is this the end of Renal Denervation?
Is this the end of Renal Denervation?
• Data base locked at end of year, preliminary results releasedresults released
• HTN 3 has met safety endpoint, but did not meet efficacy endpoint
• Independent panel of advisors to advise Medtronic on next steps
F ll D t S t ill b l d i i d• Full Data Set will be released in peer reviewed journal and presented at upcoming national meeting
Is this the end of Renal Denervation?
Is this the end of Renal Denervation?
• Enrollment suspended in 3 countries where HTN trials are ongoing (US, HTN Japan, HTN India)
HTN 4 (study at OSU is suspended)– HTN 4 (study at OSU is suspended)
• FDA – access available in 86 countries where the device is approved – discussions with regulatory bodies ongoing
• Global registry, 5000 plus patients, post market surveillance ongoing.
• Next steps for HTN-3 – follow patients for 5 years; cross over patients procedures suspended
• Other devices may still come to trial to better understand this technology
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ConclusionsConclusions• A significant percentage of hypertensive
patients are poorly controlled, but the exact prevalence of resistantexact prevalence of resistant hypertension is unknown
• In the general population aged ≥60 years, initiate pharmacologic therapy at SBP ≥150 mm Hg or DBP ≥90 mm Hg and treat g gto a goal SBP <150 mm Hg and DBP <90 mm Hg. (Strong Recommendation –Grade A)
Conclusions (continued)Conclusions (continued)
• In the general population <60 years, initiate pharmacologic therapy to at DBPinitiate pharmacologic therapy to at DBP ≥90 mm Hg and treat to a goal DBP <90 mm Hg. (For ages 30-59 years, Strong Recommendation – Grade A)
• In the general population <60 years, i i i h l i h SBPinitiate pharmacologic therapy at SBP ≥140 mm Hg and treat to a goal SBP <140 mm Hg. (Expert Opinion – Grade E)
36
Conclusions (continued)Conclusions (continued)• A majority of patients with resistant
hypertension (and no secondary cause) have an activated sympathetic nervous system and increased sympathetic outflow
• Until yesterday, preliminary efficacy data for renal denervation was promising
Conclusions (continued)Conclusions (continued)
• The Symplicity Trials reinforce the importance of blindedthe importance of blinded randomized clinical trials
• Symplicity HTN-3 was a very well designed trial that did not meet it’ ffi d i tit’s efficacy endpoint